KRIT-1 is an intracellular protein that interacts with the RAS family of GTPases. Recently loss-of-function mutations in KRIT-1 were found to be responsible for an autosomal dominant human vascular dysplasia, cerebral cavaernous malformations (CCM). My laboratory independently cloned the KRIT-1 gene in a screen for genes differentially expressed in mice lacking activin receptor-like kinase 1, Alk-1. Los of function mutations is A1k1 is responsible for another autosomal dominant vascular dysplasia, hereditary hemorrhagic telangiectasia (HM I). In both CCM and HHT, there are abnormal dilated sacs of endothelium that cause morbidity by hemorrhaging or expanding. Our previous studies demonstrated that Alk-1 regulates endothelial cell (EC) maturation and establishes arterial identity. Our identification of KRIT-I as a differentially expressed gene in Alk1 4- mice, and the involvement of both genes in the etiology of vascular dysplasias suggest that KRIT-1 mediates endothelial cell maturation and is essential for angiogenesis, we propose three specific aims. (1) Determine whether KRIT-1 is essential for vessel development by generating and characterizing gene targeted mice, (2) Examine whether KRIT-I mediates EC maturation using an in vitro cell culture system. (3) Identify novel molecular events that are downstream of KRIT-1, expressed in the endothelium, and essential for vessel development. This grant application seeks to describe a role for KRIT-1 in vascular development and define a molecular pathway for endothelial maturation. We postulate that many vascular dysplasias are the result of genetic defects along a common molecular pathway that regulates endothelial maturation. Dr. Li is an independent scientist who has made significant contributions to the study of vascular development. The NHLBI K02 Independent Scientist Award will enable him to concentrate over 90 percent of his time on research by horning his clinical, administrative and teaching responsibilities. With this time, Dr. Li will develop a new project that will enhance our fundamental understanding of vascular development and discase.